Kisspeptin (Kissi) neurons in the hypothalamus play an essential role in the maintenance of basal luteinizing hormone (LH) secretion and in generating the preovulatory gonadotropin-releasing hormone (GnRH) surge required for ovulation. The overarching goal of this proposal is to understand the physiological function of kisspeptin in the regulation of reproduction, and to evaluate its relevance for contraception and the treatment of developmental and reproductive disorders. Correspondingly, this proposal is divided in to two specific aims that will 1) address the mechanisms whereby kisspeptin neurons in the sexually differentiated anteroventral periventricular nucleus (AVPV) are activated by gonadal steroids to induce the preovulatory GnRH/LH surge, and 2) evaluate the therapeutic potential of a kisspeptin antagonist. Specifically, Aim 1 will test the hypothesis that progesterone receptor (PR) signaling in Kissi neurons of the AVPV plays an important role in gating the GnRH/LH surge. I will investigate whether the presence of estradiol (E2) up-regulates PR expression in Kissi neurons in the AVPV and whether long-term progesterone (P) treatment inhibits the activation of Kissi neurons, much as it does for the GnRH/LH surge. Additionally, I will determine whether E2 alone elicits daily activation of Kissi. Finally, I will determine whether the presence of functional PR is critical for the ability of E2 alone to repeatedly activate Kissi neurons. Aim 2 adopts a translational approach to address the utility of a recently discovered Kissir antagonist, peptide 234. This pharmacological agent has been shown to disrupt the neuroendocrine regulation of GnRH/LH secretion when injected into the cerebral ventricles;however, its ability to block central kisspeptin activity when administered outside of the blood-brain barrier has not been evaluated. I will test the efficacy of systemically administered peptide 234 in blocking the LH surge, disrupting the post- gonadectomy LH rise and estrous cyclicity, and preventing the onset of puberty. Relevance. Elucidating the significance of kisspeptin in the control of gonadotropin secretion may provide further insight into the mechanisms responsible for idiopathic hypogonadotropic hypogonadism. Moreover, this work with peptide 234 may establish the foundation for possible clinical treatments of reproductive disorders (e.g., precocious puberty, endometriosis, and metastatic prostate cancer). It is also conceivable that this knowledge might serve as the basis for the development of newer and better strategies for hormonal contraception (for both males and females) or ovulation induction.